The human gastrointestinal tract is colonized by a climax population of microbes (the gut microbiome) that interacts intimately with its host. Linkages between the gut microbiome and host metabolic and immune functions are complex and vital; aberrations in the acquisition or ultimate composition of the gut microbiome are believed to be an important predisposition factor in complex diseases such as obesity, inflammatory bowel disease, and gastric cancers later in life. Like these multifactorial diseases, composition of the gut microbiome is in itself a complex trait, affected by both environmental factors (chance, exposure, diet) and a number of host genetic factors such as those influencing mucosal immunity. The relative influence of niche-related, neutral, and historical processes in the assembly of microbial populations is currently a topic of hot debate in the field of community ecology, and these concepts are also of major significance for the microbial ecology in the gastrointestinal tract. With an integrated set of synergistic specific aims, we will explore the roe of colonization history for the assembly of the gut microbiome in mice. Our rationale for this research is that a refined understanding of how the microbiota of the gut is assembled is necessary to inform successful strategies to reshape microbiotas and counteract aberrant patterns of colonization. Our working hypothesis is that Historic Processes, and especially colonization order, are major determinants during the assembly of the gut microbiota. Our current objectives are to characterize the importance of colonization order in the assembly process of the gut microbiota, test whether the adaptive immune system influences this process, and determine if colonization order affects long-term persistence of specific 'probiotic' strains. Our innovative experiments capitalize on gnotobiotic technology and our extensive expertise in creating and evaluating complex microbial populations in experimental mice. The team represented in this proposal has forged impressive collaborations to create a new experimental approach and favorable research environments.